The immediate-type hypersensitivities, such as extrinsic asthma, hay fever, and allergic responses to certain foods or drugs, are mediated primarily by one of the immunoglobulin isotypes, i.e. , IgE. In an IgE-mediated allergic response, the allergen binds to the IgE which is bound to receptors on the surface of mast cells and basophilic leukocytes (basophils). The binding of the allergen causes crosslinking of the surface IgE molecules and hence the underlying receptors for the Fc portion of IgE (Fc.epsilon.R), thereby triggering the release of pharmacologic mediators such as histamine, the slow-reacting substance of anaphylaxis (SRA), and serotonin. The release of these mast cell and basophil products causes the pathological reactions and symptoms of allergy.
IgE is secreted by a particular class of B cells, which also express IgE on their surface. In individuals sensitized to specific allergens, the allergen-specific IgE is continuously produced by these B cells. Nevertheless, individuals who have no secreted IgE in their systems (and no IgE producing B cells) appear to live normally, indicating that IgE is not essential in the immune response. IgE may, however, be useful in fighting infection by parasites.
It seems, therefore, that reducing secreted IgE by suppressing or depleting IgE producing B cells would be a viable therapy for allergy. Monoclonal antibodies (and derivative and related products) which bind specifically to the IgE producing B cells could be used in such a suppression or elimination process. The immune system's regulatory, cytolytic or cytotoxic mechanisms can be used to suppress or destroy cells which are bound by monoclonal antibodies, or by the derivative or related products.
IgE binds to the Fc.epsilon.R receptors on the surface of basophils and mast cells very strongly, with an association constant, Ka, of about 1.times.10.sup.10 liter/mole. Even though IgE is not synthesized by basophils and mast cells, the very strong and stable association of IgE with Fc.epsilon.R means that IgE is virtually always present and exposed on the surface of these cells. Thus, an immunotherapeutic agent targeting the IgE on B cells must not react with the IgE on basophils and mast cells, in order to avoid cross-linking this IgE and the underlying Fc.epsilon.R and thereby triggering an allergic reaction.